Uterine dysfunction and disease often result from the disruption of regulated cell proliferation. As examples, endometrial carcinoma, endometrosis, and leiomyoma are all characterized by abnormal cell proliferation. In addition, insufficient or asynchronous endometrial proliferation and development is a frequent cause of infertility. If cell or tissue-specific steps in the regulation of uterine cell proliferation were known, uterine-specific regulatory molecules, could serve as the basis of targeted therapies to control proliferation and differentiation in uterine disease. As a result, side-effects which result from current therapies could be avoided. Progesterone is required to support both proliferation and differentiation (decidualization) of uterine stromal cells, but very little is known of the molecular pathways stimulated by progesterone which lead to mitosis or decidualization. We have demonstrated that heparin-binding epidermal growth factor (HB-EGF) expression is stimulated by progesterone in uterine stromal cells and that inhibiting HB-EGF function also inhibits decidualization. Therefore, progesterone and HB-EGF are the only molecules which have been demonstrated to be essential for decidualization. The proposed research project is designed to elucidate the mechanisms through which HB-EGf regulates the molecular pathway leading to uterine stromal cell proliferation, and determine how proliferation controls decidualization. Our project will test the hypothesis that decidualization is dependent on progestrone-induced stroma cell proliferation, which is mediated by HB-EGF. Specific Aim 1 will test a hypothetical proliferation pathway to determine how HB-EGF regulates stromal cell proliferation, how HB-EGF itself is regulated in this pathway, and what other proteins are essential for stromal cell proliferation. Specific Aim 2 will define steps in the proliferation pathway which are essential for decidualization by blocking specific phases of the uterine stromal cell cycle. Specific Aim 3 will test a model proliferation pathway in vivo and identify additional protein targets for therapeutic intervention. The resulting model of the molecular pathway for uterine stromal cell proliferation and decidualization will provide a basic foundation for the development of selective, targeted, therapies for uterine diseases derived from unregulated cell proliferation.